This project focuses on novel strategies for the treatment of patients with hematopoietic malignancies employing allogeneic grafts. The Project consists of four clinical trials which are developed from preclinical models mainly developed by this Program Project. In the first Specific Aim, the clinical utility of a non-myeloablative regimen will be explored for patients with myelodysplastic syndromes (MDS) and myeloproliferative disorders (MPD). This study will evaluate the overall effectiveness of this novel treatment strategy for these diseases and identify prognostic factors associated with success or failure. It is anticipated that this study will form the basis of a future phase III study comparing non-myeloablative with standard myeloablative approaches. In the second Specific Aim, a novel preparative regimen utilizing total lymphoid irradiation and anti-thymocyte globulin will be evaluated in patients with hematologic malignancies (other than MDS or MPD). This study is based upon the preclinical observations that this treatment strategy alters the host such that graft-versus-host disease (GVHD) is markedly reduced due to the rapid recovery of bone marrow derived NK-T cells which produce cytokines that reduce GVHD induction by donor-derived T cells. This concept will be explored first for patients with HLA-matched siblings and matched unrelated donors and if successful, then extended to haploidentical donors. In the third Specific Aim, we will continue our studies of utilizing purified hematopoietic stem cells (HSC) in transplantation. We have previously demonstrated our abilities to transplant highly purified HSC in the autologous setting, In the proposed trial, we will utilize highly purified HSC derived from HLA-matched sibling donors for allogeneic transplantation. We will combine HSC with defined doses of CD3+ T cells to carefully characterize the cellular components of the graft required for engraftment with minimal GVHD. In the fourth Specific Aim, the clinical activity of allogeneic cytokine induced killer (CIK) cells will be explored in place of donor leukocyte infusions. CIK cells have retained GVL effects, yet cause minimal GVHD in animal models. These studies are highly integrated with the research projects and cores of this grant.